With the advent of highly active antiretroviral therapy (HAART), the survival of individuals infected with HIV-1 has dramatically improved. However, recent recognition of the markedly accelerated development of emphysema in this population at an early age and with a minimal smoking history provides an opportunity to study the molecular basis for this problem. In this context, the emphysema of HIV-1/AIDS joins a1-antitrypsin deficiency as a clinical model of an accelerated form of lung destruction, and thus HIV-1+ individuals that smoke can serve as a model to understand the pathogenesis of emphysema. Based on the knowledge that the alveolar macrophage (AM) is the primary cell type of the lung that is chronically infected by HIV-1, and that the AM plays a central role in releasing mediators that mediate the lung destruction in smoking-ind.uced emphysema, we hypothesize that HIV-1 and cigarette smoke synergize to activate AM to express a transcriptome that is highly dangerous to the lung parenchyma. Its evaluation will help to identify the activation pathways that are most critical in the development of emphysema and represent pharmacologic targets. Based on this background, we propose to assess 3 specific aims. Aim 1. To test the hypothesis that HIV-1 infection and cigarette smoking act in concert to create a pattern of AM gene expression indicative of up-regulated expression of genes relevant to the pathogenesis of emphysema and that these changes are in excess of, or in addition to, that induced by smoking or HIV-1 alone. Aim 2. Based on the knowledge that HIV-1 infection is associated with elevated systemic and lung levels of tumor necrosis factor-a (TNF-a) and interferon-Y (IFN-v), and that expression of TNF-a or IFN-v in the lungs of experimental animals is associated with the development of emphysema, we will examine the hypothesis that the exaggerated program of emphysema-related mediators expressed by AM of HIV-1+ smokers is linked to the overexpression of TNF-a and/or IFN-y in the lung. Aim 3. To examine the hypothesis that while HAART therapy effectively suppresses replication of HIV-1 in the AM, it does not entirely suppress the pattern of gene expression of the AM relevant to the pathogenesis of emphysema, and that the persistence of the subset of up-regulated genes in the AM is linked to TNF-a or INF-v in the milieu of the alveolus.